IV fluids are recommended to adults with sepsis. However, the optimal strategy for IV fluid management in sepsis is unknown, and clinical equipoise exists.
Do lower vs higher fluid volumes improve ...patient-important outcomes in adult patients with sepsis?
We updated a systematic review with meta-analysis and trial sequential analysis of randomized clinical trials assessing lower vs higher IV fluid volumes in adult patients with sepsis. The coprimary outcomes were all-cause mortality, serious adverse events (SAEs), and health-related quality of life (HRQoL). We followed the recommendations by the Cochrane Handbook and used the Grading of Recommendations Assessment, Development and Evaluation approach. Primary conclusions were based on low risk of bias trials if available.
We included 13 trials (N = 4,006) with four trials (n = 3,385) added to this update. The meta-analysis of all-cause mortality in eight low risk of bias trials showed a relative risk of 0.99 (97% CI, 0.89-1.10; moderate certainty evidence). Six trials with predefined definitions of SAEs showed a relative risk of 0.95 (97% CI, 0.83-1.07; low certainty evidence). HRQoL was not reported.
Among adult patients with sepsis, lower IV fluid volumes probably result in little to no difference in all-cause mortality compared with higher IV fluid volumes, but the interpretation is limited by imprecision in the estimate, which does not exclude potential benefit or harm. Similarly, the evidence suggests lower IV fluid volumes result in little to no difference in serious adverse events. No trials reported on HRQoL.
PROSPERO; No.: CRD42022312572; URL: https://www.crd.york.ac.uk/prospero/.
Intravenous (IV) fluids are recommended to adults with sepsis. However, the optimal strategy for IV fluid management in sepsis is unknown, and clinical equipoise exists. Do lower vs higher fluid ...volumes improve patient-important outcomes in adult patients with sepsis?
We updated a systematic review with meta-analysis and trial sequential analysis of randomized clinical trials assessing lower vs higher IV fluid volumes in adult patients with sepsis. The co-primary outcomes were all-cause mortality, serious adverse events (SAEs), and health-related quality of life (HRQoL). We followed the recommendations by the Cochrane Handbook and used the Grading of Recommendations Assessment, Development and Evaluation approach (GRADE). Primary conclusions were based on low risk of bias (RoB) trials if available.
We included 13 trials (n = 4006) with four trials (n = 3385) added to this update. The meta-analysis of all-cause mortality in eight low RoB trials showed a relative risk (RR) 0.99 (97% CI 0.89 to 1.10; moderate certainty evidence). Six trials with predefined definitions of SAEs showed a RR 0.95 (97% CI 0.83 to 1.07; low certainty evidence). HRQoL was not reported.
Among adult patients with sepsis, lower IV fluid volumes probably result in little to no difference in all-cause mortality compared with higher IV fluid volumes, but the interpretation is limited by imprecision in the estimate, which does not exclude potential benefit or harm. Similarly, the evidence suggests lower IV fluid volumes result in little to no difference in serious adverse events. No trials reported on HRQoL.
Background
Clinical equipoise exists regarding intravenous (IV) fluid volumes in sepsis. The Conservative vs. Liberal Approach to fluid therapy of Septic Shock in Intensive Care (CLASSIC) trial ...investigates the effect of restricted vs. standard IV fluid therapy in 1554 adult intensive care unit patients with septic shock.
Methods
This protocol describes secondary Bayesian analyses of the primary outcome (90‐day all‐cause mortality) and three secondary outcomes at day 90. We will analyse all binary outcomes with adjusted Bayesian logistic regressions and present results as conditional relative risks and risk differences with 95% credibility intervals (CrIs). The secondary count outcome will be analysed using adjusted Bayesian linear regression with results summarised as conditional mean differences and ratios of means with 95% Crls. We will use weakly informative priors for the primary analyses, and sceptical and evidence‐based priors in the sensitivity analyses. Exact probabilities will be presented for any benefit/harm, clinically important benefit/harm and no clinically important difference. We will assess whether heterogeneity of treatment effects on mortality is present using Bayesian hierarchical models in subgroups and on the continuous scale using models with interactions according to five baseline variables assessing the overall severity of illness and the degree of circulatory and renal impairment.
Discussion
The outlined analyses will supplement the primary analysis of the CLASSIC trial by describing probabilities of beneficial and harmful effects and evaluating heterogeneity of treatment effects in a framework that may be easier to interpret for researchers and clinicians.
Background
Intensive care unit (ICU) patients receive numerous interventions, but knowledge about potential interactions between these interventions is limited. Co‐enrolment in randomized clinical ...trials represents a unique opportunity to investigate any such interactions. We aim to assess interactions in four randomized clinical trials with overlap in inclusion periods and patient populations.
Methods
This protocol and statistical analysis plan describes a secondary explorative analysis of interactions in four international ICU trials on pantoprazole, oxygenations targets, haloperidol and intravenous fluids, respectively. The primary outcome will be 90‐day all‐cause mortality. The secondary outcome will be days alive and out of hospital in 90 days after randomization. All patients included in the intention‐to‐treat populations of the four trials will be included. Four co‐primary analyses will be conducted, one with each of the included trials as reference using a logistic regression model adjusted for the reference trial's stratification variables and for the co‐interventions with interactions terms. The primary analytical measure of interest will be the analyses’ tests of interaction. A p‐value below .05 will be considered statically significant. The stratification variable‐ and co‐intervention‐adjusted effect estimates will be reported with 95% confidence intervals without adjustments for multiplicity.
Conclusion
This exploratory analysis will investigate the presence of any interactions between pantoprazole, oxygenation targets, haloperidol and amount of intravenous fluids in four international ICU trials using co‐enrolment. Assessment of possible interactions represents valuable information to guide the design, statistical powering and conduct of future trials.
To assess long-term outcomes of restrictive versus standard intravenous (IV) fluid therapy in adult intensive care unit (ICU) patients with septic shock included in the European Conservative versus ...Liberal Approach to Fluid Therapy in Septic Shock in Intensive Care (CLASSIC) trial.
We conducted the pre-planned analyses of mortality, health-related quality of life (HRQoL) using EuroQol (EQ)-5D-5L index values and EQ visual analogue scale (VAS), and cognitive function using Mini Montreal Cognitive Assessment (Mini MoCA) test at 1-year. Deceased patients were assigned numerical zero for HRQoL as a state equal to death and zero for cognitive function outcomes as worst possible score, and we used multiple imputation for missing data on HRQoL and cognitive function.
Among 1554 randomized patients, we obtained 1-year data on mortality in 97.9% of patients, HRQoL in 91.3%, and cognitive function in 86.3%. One-year mortality was 385/746 (51.3%) in the restrictive-fluid group versus 383/767 (49.9%) in the standard-fluid group, absolute risk difference 1.5%-points (99% confidence interval (CI) -4.8 to 7.8). Mean differences were 0.00 (99% CI -0.06 to 0.05) for EQ-5D-5L index values, −0.65 for EQ VAS (−5.40 to 4.08), and − 0.14 for Mini MoCA (−1.59 to 1.14) for the restrictive-fluid group versus the standard-fluid group. The results for survivors only were similar in both groups.
Among adult ICU patients with septic shock, restrictive versus standard IV fluid therapy resulted in similar survival, HRQoL and cognitive function at one year, but clinically important differences could not be ruled out.
IV fluids are recommended for adults with sepsis. However, the optimal strategy for IV fluid management in sepsis is unknown, and clinical equipoise exists.
Do lower vs higher fluid volumes improve ...patient-important outcomes in adult patients with sepsis?
We updated a systematic review with meta-analysis and trial sequential analysis of randomized clinical trials assessing lower vs higher IV fluid volumes in adult patients with sepsis. The coprimary outcomes were all-cause mortality, serious adverse events, and health-related quality of life. We followed the recommendations from the Cochrane Handbook and used the Grading of Recommendations Assessment, Development and Evaluation approach. Primary conclusions were based on trials with low risk of bias if available.
We included 13 trials (N = 4,006) with four trials (n = 3,385) added to this update. The meta-analysis of all-cause mortality in eight trials with low risk of bias showed a relative risk of 0.99 (97% CI, 0.89-1.10; moderate certainty evidence). Six trials with predefined definitions of serious adverse events showed a relative risk of 0.95 (97% CI, 0.83-1.07; low certainty evidence). Health-related quality of life was not reported.
Among adult patients with sepsis, lower IV fluid volumes probably result in little to no difference in all-cause mortality compared with higher IV fluid volumes, but the interpretation is limited by imprecision in the estimate, which does not exclude potential benefit or harm. Similarly, the evidence suggests lower IV fluid volumes result in little to no difference in serious adverse events. No trials reported on health-related quality of life.
PROSPERO; No.: CRD42022312572; URL: https://www.crd.york.ac.uk/prospero/
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To the Editor:
In the Conservative versus Liberal Approach to Fluid Therapy of Septic Shock in Intensive Care (CLASSIC) trial, Meyhoff et al. (June 30 issue)
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found similar numbers of death at 90 ...days in patients with septic shock who received resuscitation with a restrictive-fluid strategy (42.3%) and in those who received resuscitation with a liberal-fluid (standard) approach (42.1%). Because resuscitative fluids were allowed to be used in the restrictive-fluid group only in the case of severe hypoperfusion — requiring, among other signs, a mean arterial pressure of less than 50 mm Hg despite administration of vasopressor agents or inotropes . . .
To develop and validate Clinical Diversity In Meta-analyses (CDIM), a new tool for assessing clinical diversity between trials in meta-analyses of interventions.
The development of CDIM was based on ...consensus work informed by empirical literature and expertise. We drafted the CDIM tool, refined it, and validated CDIM for interrater scale reliability and agreement in three groups.
CDIM measures clinical diversity on a scale that includes four domains with 11 items overall: setting (time of conduct/country development status/units type); population (age, sex, patient inclusion criteria/baseline disease severity, comorbidities); interventions (intervention intensity/strength/duration of intervention, timing, control intervention, cointerventions); and outcome (definition of outcome, timing of outcome assessment). The CDIM is completed in two steps: first two authors independently assess clinical diversity in the four domains. Second, after agreeing upon scores of individual items a consensus score is achieved. Interrater scale reliability and agreement ranged from moderate to almost perfect depending on the type of raters.
CDIM is the first tool developed for assessing clinical diversity in meta-analyses of interventions. We found CDIM to be a reliable tool for assessing clinical diversity among trials in meta-analysis.
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